Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Elias WJ, Huss D, Voss T, et al. A pilot study of focused ultrasound thalamotomy for essential tremor. N Engl J Med 2013;369:640-8. DOI: 10.1056/NEJMoa1300962
Supplementary Appendix A Pilot Study of Focused Ultrasound Thalamotomy for Essential Tremor W. Jeffrey Elias MD 1, Diane Huss PT DPT NCS 2, Tiffini Voss MD 3, Johanna Loomba BS 1, Mohamad Khaled MD 1, Eyal Zadicario Msc 5, Robert C. Frysinger PhD 1, Scott A. Sperling Psy.D 3, Scott Wylie PhD 3, Stephen Monteith MD 1, Jason Druzgal MD PhD 4, Binit B. Shah MD 3, Madaline Harrison MD 3, and Max Wintermark MD 4 1 Departments of Neurosurgery, 2 Physical Therapy, 3 Neurology, and 4 Neuroradiology University of Virginia Health Sciences Center, Charlottesville, VA 5 Insightec Inc., Haifa, Israel 1
Table of Contents Table S1. Individual tremor scores: contralateral (treated) upper limb 3 Table S2. Individual tremor scores: Total Clinical Rating Scale for Tremor 4 Table S3. Dynamic Gait Index scores 5 Figure S1. Workflow illustration of transcranial MR-guided focused ultrasound for the treatment of tremor 6 Figure S2. Individual drawing and handwriting tasks 7-22 References 23 2
Table S1. Individual Tremor Scores: Contralateral (Treated) Upper Limb Reference # Baseline Tx Day pre Tx Day post 24 Hr 1 Wk 1 Mo 3 Mo 1 Yr % Δ Baseline - 1Yr ET-001 20 24 0 0 0 0 1 0 100 ET-002 19 23 0 0 0 3 1 1 95 ET-003 12 13 0 1 1 1 2 1 92 ET-004 18 17 2 0 0 0 0 2 89 ET-005 16 13 2 1 1 0 2 2 88 ET-006 14 14 6 2 0 0 2 2 86 ET-007 20 22 2 3 2 3 3 3* 85 ET-008 28 27 3 0 0 1 1 5 82 ET-009 24 22 10 2 5 4 7 5 79 ET-010 29 31 9 8 5 6 6 6 79 ET-011 22 25 5 2 3 6 6 8 64 ET-012 20 21 0 0 3 7 6 9 55 ET-013 21 20 7 2 6 8 9 10 52 ET-014 28 28 4 2 2 10 7 17 39 ET-015 15 20 5 7 4 8 12 11 27 Mean 20.4 21.3 3.7 2.0 2.1 3.8 4.3 5.2 75 St. Dev. 5.2 5.4 3.3 2.4 2.1 3.5 3.5 4.8 The maximum score is 32 points for eight items each with a score range from 0-4. The eight items include treated side (contralateral to the thalamotomy) observed tremor in rest, posture and action/intention from part A of the Clinical Rating Scale for Tremor 1 and the part B tasks of handwriting, two targeted spiral drawings, one line drawing, and water pouring. Supplemental results are listed in order of treatment response of the treated hand. Patient reference numbers are consistent throughout the Supplemental Figures and Tables. Note immediate decline in tremor as tested within 30 minutes of completion of treatment (Tx Day post). Ten individuals demonstrated additional decline at one week, likely due to perilesional edema confirmed on MRI at one week. One year after treatment, 11 individuals scored ±2 points of their one month score. While a minimal detectable change score has not been reported for the Clinical Rating Scale for Tremor, the relative stability of their tremor control is consistent with their continued abilities as noted in in part C of the Clinical Rating Scale for Tremor and on the Quality of Life for Essential Tremor Questionnaire. (Figure 1) One person gained 3 points, another 4 points and a third increased by 7 points. Only the later, reported concurrent decline in functional abilities with the increased tremor. The other two continued to report little to no functional disability. *One patient did not return for a one year assessment. His last observed score was carried forward. 3
Table S2. Individual Tremor Scores: Total Score Reference # Baseline 1 Wk 1 Mo 3 Mo 1 Yr % Δ Baseline - 1Yr ET-001 53 6 2 6 6 89 ET-002 44 7 9 8 11 75 ET-003 39 13 11 15 15 62 ET-004 38 12 11 8 9 76 ET-005 49 14 9 16 17 65 ET-006 47 10 10 15 20 57 ET-007 44 21 19 22 22* 50 ET-008 60 18 12 12 20 67 ET-009 52 15 16 17 15 71 ET-010 87 43 39 37 43 51 ET-011 68 40 35 35 44 35 ET-012 55 10 13 15 15 73 ET-013 60 21 30 30 36 40 ET-014 81 27 39 35 55 32 ET-015 47 20 25 34 37 21 Mean 54.9 18.5 18.7 20.3 24.3 56 St. Dev. 14.4 11.0 12.0 11.0 14.8 Maximum tremor score from the Clinical Rating Scale for Tremor is 160 with a higher score indicating more overall tremor throughout the body. This score summates overall tremor from contralateral and ipsilateral limbs as well as axial tremors of the head, neck, voice, and trunk. Overall average improvement is 56% with range from 89% to 21%. The greatest degree of tremor suppression on this total/overall score tended to occur in patients with asymmetrical and predominantly appendicular tremor. Given that this is a unilateral treatment and the condition is progressive, it is difficult to discern solely from this Table whether an increasing total tremor score results from recurrence in the treated limb or progression of disease in the untreated regions. *Last observed score carried forward. 4
Table S3. Dynamic Gait Index 2 Scores Reference # Baseline 1 Wk 1 Mo 3 Mo 1 Yr ET-001 21 18 24 24 24 ET-002 16 19 21 23 24 ET-003 22 16 22 22 20 ET-004 24 24 23 24 24 ET-005 24 24 23 24 24 ET-006 17 17 20 18 19 ET-007 22 22 23 23* 23 ET-008 24 22 21 23 23 ET-009 24 23 23 24 24 ET-010 15 21 15 19 14 ET-011 22 13 22 21 24 ET-012 19 24 24 23 21 ET-013 24 23 22 23 23 ET-014 22 18 24 24 23 ET-015 23 24 24 23 24 Mean 21.2 20.6 22.1 22.5 22.3 St. Dev. 3.1 3.6 2.3 1.9 2.8 Objective declines in gait and balance stability at one week post treatment in four patients (highlighted) which were classified as a gait ataxia. In all four cases, the instability resolved by one month. Five other patients reported temporary unsteadiness without an objective change in their gait performance. The Dynamic Gait Index has a maximum of 24 points with a minimal detectible change score ±2.9 (MDC 95% ). 1 This represents a 95% confidence level that genuine change in function has occurred between two assessments. *Last observed score carried forward. 5
Figure S1. Workflow Illustration of Transcranial MR-guided Focused Ultrasound for the Treatment of Tremor. Note that closed loop feedback is available throughout the procedure. (Center) Hemispherical transducer with 1024 elements capable of focusing acoustic energy through the intact cranium. (Left) Stereotactic planning is performed from high resolution 3 Tesla MR images. (Upper) Series of MR thermal images acquired every 3.7 seconds during a single sonication which allows clinicians the ability to measure the intensity of the treatment to within 1⁰ Celsius as well as to monitor the location of the treatment. (Right and bottom) Clinical testing is conducted with each sonication to verify tremor relief or the development of side effects. 6
Figure S2. Individual drawing and handwriting samples for all 15 subjects. These samples are obtained from the Clinical Rating Scale for Tremor part B subsection administered at baseline, pretreatment day, immediately posttreatment on the same day, one month, three months, and one year. These drawings and handwriting tasks depict immediate abatement of tremor post treatment with ongoing follow up at one month, three months and one year. Treated hand (contralateral to thalamotomy) and untreated hand (ipsilateral to thalamotomy) are represented. 7
ET-001 8
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ET-008 15
ET-009 16
ET010 17
ET-011 18
ET-012 19
ET-013 20
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ET-015 22
REFERENCES 1. Fahn S, Tolosa E, Marin C. Clinical Rating Scale for Tremor: Parkinson s Disease and Movement Disorders: edited by Jankovic J and Tolosa E 2 nd ed, Baltimore: Williams and Wilkins; 1993. 2. Shumway-Cook A, Woollacott M. Motor Control: Theory and Practical Applications. Baltimore: Williams and Wilkins; 1995. 3. Romero S; Bishop MD, Velozo CA, Light K. Minimum detectable change of the Berg Balance Scale and dynamic gait index in older persons at risk for falling. Journal of geriatric physical therapy 2011;34:131-137. 23